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Protein

Protective antigen

Gene

pagA

Organism
Bacillus anthracis
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

One of the three proteins composing the anthrax toxin, the agent which infects many mammalian species and that may cause death. PA binds to a receptor (ATR) in sensitive eukaryotic cells, thereby facilitating the translocation of the enzymatic toxin components, edema factor and lethal factor, across the target cell membrane. PA associated with LF causes death when injected, PA associated with EF produces edema. PA induces immunity to infection with anthrax.

Miscellaneous

In PubMed:10085028 multiple mutagenesis experiments were performed that showed that the residues present in the small loop of domain 4, and not the ones in the large loop, are involved in receptor recognition. In PubMed:14623961 high-throughput scanning mutagenesis experiments were performed in which all residues of PA-63 were mutated into Cys. Dominantly negative (DN) mutants were all clustered in domain 2. DN mutants prevent the conformational transition of PA-63 from the prepore to the pore state.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi206Calcium1
Metal bindingi208Calcium1
Metal bindingi210Calcium1
Metal bindingi217Calcium1
Sitei712Essential for binding to cell receptor1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionToxin
Biological processVirulence
LigandCalcium, Metal-binding

Enzyme and pathway databases

ReactomeiR-HSA-5210891 Uptake and function of anthrax toxins

Protein family/group databases

TCDBi1.C.42.1.1 the channel-forming bacillus anthracis protective antigen (bapa) family

Names & Taxonomyi

Protein namesi
Recommended name:
Protective antigen
Short name:
PA
Alternative name(s):
Anthrax toxins translocating protein
PA-83
Short name:
PA83
Cleaved into the following 2 chains:
Protective antigen PA-20
Short name:
PA20
Protective antigen PA-63
Short name:
PA63
Gene namesi
Name:pagA
Synonyms:pag
Ordered Locus Names:pXO1-110, BXA0164, GBAA_pXO1_0164
Encoded oniPlasmid pXO10 Publication
OrganismiBacillus anthracis
Taxonomic identifieri1392 [NCBI]
Taxonomic lineageiBacteriaFirmicutesBacilliBacillalesBacillaceaeBacillusBacillus cereus group
Proteomesi
  • UP000000594 Componenti: Plasmid pXO1

Subcellular locationi

  • extracellular space
  • Note: Secreted through the Sec-dependent secretion pathway. Therefore, PA is translocated across the membrane in an unfolded state and then it is folded into its native configuration on the trans side of the membrane, prior to its release to the environment. PA requires the extracellular chaperone PrsA for efficient folding.

GO - Cellular componenti

Keywords - Cellular componenti

Secreted

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi213P → A: Decrease in the ability to bind to LF and partially toxic at high concentrations. 1 Publication1
Mutagenesisi216L → A: Decrease in the ability to bind to LF and partially toxic at high concentrations. 1 Publication1
Mutagenesisi231F → A: Loss of ability to bind to LF and completely nontoxic. 1 Publication1
Mutagenesisi232L → A: Loss of ability to bind to LF and completely nontoxic. 1 Publication1
Mutagenesisi234P → A: Loss of ability to bind to LF and completely nontoxic. 1 Publication1
Mutagenesisi236I → A: Loss of ability to bind to LF and completely nontoxic. 1 Publication1
Mutagenesisi239I → A: Decrease in the ability to bind to LF and partially toxic at high concentrations. 1 Publication1
Mutagenesisi255W → A: No effect on LF-binding ability and as toxic as the wild-type. 1 Publication1
Mutagenesisi265F → A: No effect on LF-binding ability and as toxic as the wild-type. 1 Publication1
Mutagenesisi289P → A: Reduced toxicity in combination with lethal factor. Decreased membrane insertion and translocation of LF. 1 Publication1
Mutagenesisi342 – 344FFD → AAA: Decrease in toxicity probably due to slow translocation of LF. 1 Publication3
Mutagenesisi342 – 343Missing : Loss of toxicity probably due to loss of capability to translocate LF. 1 Publication2
Mutagenesisi342F → C: Loss of toxicity probably due to loss of capability to translocate LF. 1 Publication1
Mutagenesisi344D → A: Decrease in toxicity probably due to slow translocation of LF. 1 Publication1
Mutagenesisi375W → A: Loss of toxicity probably due to faulty membrane insertion or translocation of LF/EF into the cytosol. 1 Publication1
Mutagenesisi379M → A: No effect. 1 Publication1
Mutagenesisi381L → A: Loss of toxicity probably due to faulty membrane insertion or translocation of LF/EF into the cytosol. 1 Publication1
Mutagenesisi393I → C: Loss of capability to undergo conformational changes that lead to pore formation and translocation. 1 Publication1
Mutagenesisi409T → C: Loss of capability to undergo conformational changes that lead to pore formation and translocation. 1 Publication1
Mutagenesisi411S → C: Loss of capability to undergo conformational changes that lead to pore formation and translocation. 1 Publication1
Mutagenesisi422T → C: Loss of capability to undergo conformational changes that lead to pore formation and translocation. 1 Publication1
Mutagenesisi426K → A or D: Loss of capability to undergo conformational changes that lead to pore formation and translocation. 2 Publications1
Mutagenesisi428N → C: Loss of capability to undergo conformational changes that lead to pore formation and translocation. 1 Publication1
Mutagenesisi440Y → C: Loss of capability to undergo conformational changes that lead to pore formation and translocation. 1 Publication1
Mutagenesisi451N → C: Loss of capability to undergo conformational changes that lead to pore formation and translocation. 1 Publication1
Mutagenesisi454D → A or K: Loss of capability to undergo conformational changes that lead to pore formation and translocation. 2 Publications1
Mutagenesisi456F → A: Loss of capability to undergo conformational changes that lead to pore formation and translocation. 2 Publications1
Mutagenesisi512Q → A: Loss of heptamerization capability. 1 Publication1
Mutagenesisi541D → A: Loss of heptamerization capability. 1 Publication1
Mutagenesisi543L → A: Decrease in heptamerization capability. 1 Publication1
Mutagenesisi581F → A: Loss of toxicity due to defective oligomerization. 1 Publication1
Mutagenesisi583F → A: Decrease in toxicity due to defective oligomerization. 1 Publication1
Mutagenesisi591I → A: Loss of toxicity due to defective oligomerization. 1 Publication1
Mutagenesisi595L → A: Loss of toxicity due to defective oligomerization. 1 Publication1
Mutagenesisi603I → A: Loss of toxicity due to defective oligomerization. 1 Publication1
Mutagenesisi621R → A: No effect. 1 Publication1
Mutagenesisi686N → A: Decrease in toxicity due to decrease in cell binding. 1 Publication1
Mutagenesisi708K → A: No effect on toxicity. 1 Publication1
Mutagenesisi709K → A: Slight decrease in toxicity. 1 Publication1
Mutagenesisi710Y → A: Great decrease in toxicity due to decrease in cell binding. 1 Publication1
Mutagenesisi711N → A: Loss of toxicity due to decrease in cell binding. 1 Publication1
Mutagenesisi712D → A: Loss of toxicity due to decrease in cell binding. 1 Publication1
Mutagenesisi713K → A: No effect on toxicity. 1 Publication1
Mutagenesisi714L → A: No effect on toxicity. 1 Publication1
Mutagenesisi715P → A: Great decrease in toxicity due to decrease in cell binding. 1 Publication1
Mutagenesisi716L → A: Decrease in toxicity due to decrease in cell binding. 1 Publication1
Mutagenesisi717Y → A: No effect on toxicity. 1 Publication1
Mutagenesisi718I → A: Decrease in toxicity due to decrease in cell binding. 1 Publication1
Mutagenesisi719S → A: No effect on toxicity. 1 Publication1
Mutagenesisi720N → A: No effect on toxicity. 1 Publication1
Mutagenesisi721P → A: No effect on toxicity. 1 Publication1
Mutagenesisi722N → A: No effect on toxicity. 1 Publication1

Chemistry databases

ChEMBLiCHEMBL5352
DrugBankiDB09057 Anthrax immune globulin human
DB08902 Raxibacumab

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 29Add BLAST29
ChainiPRO_000002199630 – 764Protective antigenAdd BLAST735
ChainiPRO_000002199730 – 196Protective antigen PA-20Add BLAST167
ChainiPRO_0000021998197 – 764Protective antigen PA-63Add BLAST568

Post-translational modificationi

Proteolytic activation by furin or a furin-like protease cleaves the protein in two parts, PA-20 and PA-63; the latter is the mature protein. The cleavage occurs at the cell surface and probably in the serum of infected animals as well; both native and cleaved PA are able to bind to the cell receptor. The release of PA20 from the remaining receptor-bound PA63 exposes the binding site for EF and LF, and promotes oligomerization and internalization of the protein.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei196 – 197Cleavage; by furin2
Sitei343 – 344Cleavage; by chymotrypsin; required for translocation of LF and EF2

Keywords - PTMi

Cleavage on pair of basic residues

Proteomic databases

PRIDEiP13423

Miscellaneous databases

PMAP-CutDBiP13423

Interactioni

Subunit structurei

Anthrax toxins are composed of three distinct proteins, a protective antigen (PA), a lethal factor (LF) and an edema factor (EF). None of these is toxic by itself. PA+LF forms the lethal toxin (LeTx); PA+EF forms the edema toxin (EdTx). PA-63 forms heptamers and this oligomerization is required for LF or EF binding. This complex is endocytosed by the host. Once activated, at low pH, the heptamer undergoes conformational changes and converts from prepore to pore inserted in the membrane, forming cation-selective channels and triggering the release of LF and EF in the host cytoplasm.2 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

DIPiDIP-29841N
IntActiP13423, 16 interactors
MINTiP13423

Chemistry databases

BindingDBiP13423

Structurei

Secondary structure

1764
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliP13423
SMRiP13423
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP13423

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini43 – 179PA14PROSITE-ProRule annotationAdd BLAST137

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni30 – 287Domain 1, calcium-binding; LF and EF binding sitesAdd BLAST258
Regioni288 – 516Domain 2, membrane insertion and heptamerizationAdd BLAST229
Regioni517 – 624Domain 3, heptamerizationAdd BLAST108
Regioni625 – 764Domain 4, binding to the receptorAdd BLAST140

Domaini

The molecule is folded into four functional domains. Each domain is required for a particular step in the toxicity process. Domain 1 contains two calcium ions and the proteolytic activation site. Cleavage of the PA monomer releases the subdomain 1a, which is the N-terminal fragment of 20-kDa (PA20). The subdomain 1b is part of the remaining 63-kDa fragment (PA63) and contains the binding sites for LP and EF. Domain 2 is a beta-barrel core containing a large flexible loop that has been implicated in membrane insertion and pore formation. There is a chymotrypsin cleavage site in this loop that is required for toxicity. Domain 3 has a hydrophobic patch thought to be involved in protein-protein interactions. Domain 4 appears to be a separate domain and shows limited contact with the other three domains: it would swing out of the way during membrane insertion. It is required for binding to the receptor; the small loop is involved in receptor recognition.1 Publication

Sequence similaritiesi

Belongs to the bacterial binary toxin family.Curated

Keywords - Domaini

Signal

Phylogenomic databases

HOGENOMiHOG000034566
KOiK11030

Family and domain databases

Gene3Di2.60.120.240, 1 hit
InterProiView protein in InterPro
IPR003896 Bacterial_exotoxin_B
IPR035331 Binary_toxB_3
IPR037524 PA14/GLEYA
IPR011658 PA14_dom
IPR035088 PA_Ca-bd
IPR027439 PA_heptamer_dom
IPR037149 PA_heptamer_dom_sf
PfamiView protein in Pfam
PF03495 Binary_toxB, 1 hit
PF17475 Binary_toxB_2, 1 hit
PF17476 Binary_toxB_3, 1 hit
PF07691 PA14, 1 hit
PRINTSiPR01391 BINARYTOXINB
SMARTiView protein in SMART
SM00758 PA14, 1 hit
PROSITEiView protein in PROSITE
PS51820 PA14, 1 hit

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P13423-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MKKRKVLIPL MALSTILVSS TGNLEVIQAE VKQENRLLNE SESSSQGLLG
60 70 80 90 100
YYFSDLNFQA PMVVTSSTTG DLSIPSSELE NIPSENQYFQ SAIWSGFIKV
110 120 130 140 150
KKSDEYTFAT SADNHVTMWV DDQEVINKAS NSNKIRLEKG RLYQIKIQYQ
160 170 180 190 200
RENPTEKGLD FKLYWTDSQN KKEVISSDNL QLPELKQKSS NSRKKRSTSA
210 220 230 240 250
GPTVPDRDND GIPDSLEVEG YTVDVKNKRT FLSPWISNIH EKKGLTKYKS
260 270 280 290 300
SPEKWSTASD PYSDFEKVTG RIDKNVSPEA RHPLVAAYPI VHVDMENIIL
310 320 330 340 350
SKNEDQSTQN TDSQTRTISK NTSTSRTHTS EVHGNAEVHA SFFDIGGSVS
360 370 380 390 400
AGFSNSNSST VAIDHSLSLA GERTWAETMG LNTADTARLN ANIRYVNTGT
410 420 430 440 450
APIYNVLPTT SLVLGKNQTL ATIKAKENQL SQILAPNNYY PSKNLAPIAL
460 470 480 490 500
NAQDDFSSTP ITMNYNQFLE LEKTKQLRLD TDQVYGNIAT YNFENGRVRV
510 520 530 540 550
DTGSNWSEVL PQIQETTARI IFNGKDLNLV ERRIAAVNPS DPLETTKPDM
560 570 580 590 600
TLKEALKIAF GFNEPNGNLQ YQGKDITEFD FNFDQQTSQN IKNQLAELNA
610 620 630 640 650
TNIYTVLDKI KLNAKMNILI RDKRFHYDRN NIAVGADESV VKEAHREVIN
660 670 680 690 700
SSTEGLLLNI DKDIRKILSG YIVEIEDTEG LKEVINDRYD MLNISSLRQD
710 720 730 740 750
GKTFIDFKKY NDKLPLYISN PNYKVNVYAV TKENTIINPS ENGDTSTNGI
760
KKILIFSKKG YEIG
Length:764
Mass (Da):85,811
Last modified:October 18, 2001 - v2
Checksum:i3AE1EFBF48FAA03F
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti314Q → E in AAA22637 (PubMed:3148491).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural varianti295M → I in strain: PAI. 1
Natural varianti392N → D in strain: PAI. 1
Natural varianti560F → L in Sverdlovsk sample. 1
Natural varianti565P → S in strain: BA1024. 1
Natural varianti600A → V in strain: BA1024, V770-NP1-R, Carbosap and Ferrara. 1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M22589 Genomic DNA Translation: AAA22637.1
AF306778 Genomic DNA Translation: AAG24446.1
AF306779 Genomic DNA Translation: AAG24447.1
AF306780 Genomic DNA Translation: AAG24448.1
AF306781 Genomic DNA Translation: AAG24449.1
AF306782 Genomic DNA Translation: AAG24450.1
AF306783 Genomic DNA Translation: AAG24451.1
AF268967 Genomic DNA Translation: AAF86457.1
AF065404 Genomic DNA Translation: AAD32414.1
AE011190 Genomic DNA Translation: AAM26109.1
AE017336 Genomic DNA Translation: AAT28905.2
AJ413936 Genomic DNA Translation: CAC93934.1
AJ413937 Genomic DNA Translation: CAC93935.1
AB125961 Genomic DNA Translation: BAD14937.1
PIRiI39934
RefSeqiNP_052806.1, NC_001496.1
WP_000746486.1, NZ_QPKQ01000017.1
WP_000746487.1, NZ_QAEM01000007.1
WP_000746488.1, NZ_QANP01000007.1

Genome annotation databases

EnsemblBacteriaiAAM26109; AAM26109; BX_A0164
AAT28905; AAT28905; GBAA_pXO1_0164
GeneIDi3361714
KEGGibar:GBAA_pXO1_0164

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M22589 Genomic DNA Translation: AAA22637.1
AF306778 Genomic DNA Translation: AAG24446.1
AF306779 Genomic DNA Translation: AAG24447.1
AF306780 Genomic DNA Translation: AAG24448.1
AF306781 Genomic DNA Translation: AAG24449.1
AF306782 Genomic DNA Translation: AAG24450.1
AF306783 Genomic DNA Translation: AAG24451.1
AF268967 Genomic DNA Translation: AAF86457.1
AF065404 Genomic DNA Translation: AAD32414.1
AE011190 Genomic DNA Translation: AAM26109.1
AE017336 Genomic DNA Translation: AAT28905.2
AJ413936 Genomic DNA Translation: CAC93934.1
AJ413937 Genomic DNA Translation: CAC93935.1
AB125961 Genomic DNA Translation: BAD14937.1
PIRiI39934
RefSeqiNP_052806.1, NC_001496.1
WP_000746486.1, NZ_QPKQ01000017.1
WP_000746487.1, NZ_QAEM01000007.1
WP_000746488.1, NZ_QANP01000007.1

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1ACCX-ray2.10A30-764[»]
1T6BX-ray2.50X30-764[»]
1TX5model-C30-764[»]
1TZNX-ray4.30A/B/C/D/E/F/G/H/I/J/K/L/M/O203-764[»]
1TZOX-ray3.60A/B/C/D/E/F/G/H/I/J/K/L/M/O203-764[»]
1V36model-A/B/C/D/E/F/G197-764[»]
3ETBX-ray3.80J/K/L/M621-764[»]
3INOX-ray1.95A/B624-764[»]
3J9Celectron microscopy2.90A203-764[»]
3KWVX-ray3.10A/B/D/E197-764[»]
3MHZX-ray1.70A30-764[»]
3Q8AX-ray3.13A30-764[»]
3Q8BX-ray2.00A30-764[»]
3Q8CX-ray2.85A30-764[»]
3Q8EX-ray2.10A30-764[»]
3Q8FX-ray2.10A30-764[»]
3TEWX-ray1.45A30-764[»]
3TEXX-ray1.70A30-764[»]
3TEYX-ray2.12A30-764[»]
3TEZX-ray1.83A30-764[»]
4EE2X-ray1.91A30-764[»]
4H2AX-ray1.62A30-764[»]
4NAMX-ray1.70A30-764[»]
5FR3X-ray1.94A43-764[»]
ProteinModelPortaliP13423
SMRiP13423
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-29841N
IntActiP13423, 16 interactors
MINTiP13423

Chemistry databases

BindingDBiP13423
ChEMBLiCHEMBL5352
DrugBankiDB09057 Anthrax immune globulin human
DB08902 Raxibacumab

Protein family/group databases

TCDBi1.C.42.1.1 the channel-forming bacillus anthracis protective antigen (bapa) family

Proteomic databases

PRIDEiP13423

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsemblBacteriaiAAM26109; AAM26109; BX_A0164
AAT28905; AAT28905; GBAA_pXO1_0164
GeneIDi3361714
KEGGibar:GBAA_pXO1_0164

Phylogenomic databases

HOGENOMiHOG000034566
KOiK11030

Enzyme and pathway databases

ReactomeiR-HSA-5210891 Uptake and function of anthrax toxins

Miscellaneous databases

EvolutionaryTraceiP13423
PMAP-CutDBiP13423
PROiPR:P13423

Family and domain databases

Gene3Di2.60.120.240, 1 hit
InterProiView protein in InterPro
IPR003896 Bacterial_exotoxin_B
IPR035331 Binary_toxB_3
IPR037524 PA14/GLEYA
IPR011658 PA14_dom
IPR035088 PA_Ca-bd
IPR027439 PA_heptamer_dom
IPR037149 PA_heptamer_dom_sf
PfamiView protein in Pfam
PF03495 Binary_toxB, 1 hit
PF17475 Binary_toxB_2, 1 hit
PF17476 Binary_toxB_3, 1 hit
PF07691 PA14, 1 hit
PRINTSiPR01391 BINARYTOXINB
SMARTiView protein in SMART
SM00758 PA14, 1 hit
PROSITEiView protein in PROSITE
PS51820 PA14, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiPAG_BACAN
AccessioniPrimary (citable) accession number: P13423
Secondary accession number(s): Q937W2
, Q937W3, Q9F5R7, Q9KH69, Q9RQU2
Entry historyiIntegrated into UniProtKB/Swiss-Prot: January 1, 1990
Last sequence update: October 18, 2001
Last modified: November 7, 2018
This is version 181 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programProkaryotic Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Plasmid, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
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